Naturally occurring and synthetic estrogens have broad therapeutic utility, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues.
This invention relates to processes for making intermediates of estrogen receptor modulator compounds. The processes involve new methods for annelating 5-, 6- and 7-membered cycloalkenones onto an indanone.
The present invention relates to processes for the synthesis of compounds of formula I: 
The present invention relates to processes for the synthesis of compounds of formula I: 
wherein R1 is hydrogen, C1-10alkyl, C3-7cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, (heteroaryl)alkyl or SiRaRbRc wherein said alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with 1, 2 or 3 groups selected from fluoro, chloro, bromo, iodo, ORd, NReRf, O(Cxe2x95x90O)NReRf, NRe(Cxe2x95x90O)Rf, NRe(Cxe2x95x90O)ORf, SRe, S(O)Re, SO2Re, SO2NReRf, LRg or MLRg;
R2 is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF3;
R3 is hydrogen, C1-10alkyl, benzyl or a removable hydroxyl protecting group;
R4 is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF3;
R5 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-6cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl or (hetereoaryl)alkyl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl and (heteroaryl)alkyl groups are optionally substituted with bromo, iodo, ORd, SRe, 1-3 C1-3alkyl, 1-3 chloro or 1-5 fluoro;
Ra, Rb, and Rc are independently selected from C1-8alkyl, O(C1-8alkyl) and phenyl;
Rd is a removable hydroxyl protecting group, C1-10alkyl, benzyl or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C1-4alkyl, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2 or halo;
Re is C1-10alkyl or phenyl, wherein said alkyl group is optionally substituted with a group selected from O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2, phenyl or 1-5 fluoro, and wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C1-4alkyl, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2 or halo;
Rf is C1-10alkyl or phenyl, wherein said phenyl group is substituted with 1-3 substituents independently selected from C1-4alkyl, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2 or halo;
or Re and Rf, whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;
Rg is NReRf, ORd, NRe(Cxe2x95x90O)Rf, CONReRf, SO2NReRf or a 4-9 membered mono- or bicyclic N-heterocycloalkyl ring that can be optonally substituted with 1-3 C1-3alkyl and can be optionally interrupted by O, S or NRe;
L is CH2, CReRf, or C2-6alkylene, wherein said alkylene linker can be optionally interrupted by O, S or NRe;
M is O, S, NRe, NRe(Cxe2x95x90O) or (Cxe2x95x90O)NRe;
and n is one, two or three.
The first step in the synthesis of compounds of formula I comprises alkylating of an indanone of formula II to yield an intermediate of formula III. 
The alkylation is performed with an alkylating agent of formula VII in the presence of a base, 
wherein X is Br, Cl, I, OMs, OTs or OTf, and n is as defined above. Suitable bases include, but are not limited to sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide.
It is also possible to control the absolute stereochemistry of the chiral center which is generated in this alkylation reaction (indicated by an asterik in formula II). In this case, sodium or potassium hydroxide is used as a base in the presence of a chiral phase transfer catalyst. Suitable chiral phase transfer catalysts include, but are not limited to, N-benzylcinchoninium bromide, N-(p-trifluorobenzyl)cinchoninium bromide, N-(3,4-dichlorobenzyl)cinchoninium chloride, N-benzylcinchonidinium bromide, N-(p-trifluorobenzyl)cinchonidinium bromide or N-(3,4-dichlorobenzyl)cinchonidinium chloride.
Next, adding a nucleophile to an intermediate of formula III to yields a diene of formula IV. 
The nucleophilic addition can be performed with an alkenyl metal species of formula VIII, 
wherein Mxe2x80x2 is MgBr, Li or Ce, and R1 is as defined above.
The next step is cyclizing the compound of formula IV via a ring closing olefin metathesis reaction to yield an allylic alcohol of formula V. 
The ring closing olefin metathesis reaction is performed in the presence of a transition metal catalyst. Suitable transition metal catalysts include, but are not limited to: 
wherein 
A preferred transition metal catalyst is 
tricyclohexylphosphine[1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine ruthenium(IV) dichloride 
wherein
Other suitable catalysts for this ring closing olefin metathesis reaction are known in the art and are described in the following literature references [Angew. Chem. Int. Ed. 2002, 41, 794; J. Am. Chem. Soc. 2002, 124, 7061; Angew. Chem. Int. Ed. 2002, 41, 2403; J. Am. Chem. Soc. 2000, 122, 8168; Org. Lett. 2001, 3, 3225].
Alternatively, a chiral metathesis catalyst can be used during the ring closing olefin metathesis reaction. Suitable chiral metathesis catalysts include, but are not limited to: 
wherein 
The following step comprises rearranging the compound of formula I via an allylic oxidative rearrangement to yield the enone of formula VI. 
The allylic oxidative rearrangement is performed with a chromium (IV) oxidant. Suitable chromium (IV) oxidants include, but are not limited to, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide and chromium trioxide-pyridine complex.
Depending on the R3 chosen, the compound of formula VI may be equivalent to a compound of formula I. In the case where R3 is hydrogen, final deprotection may be required to give a compound of formula I.
Another embodiment of the present invention relates to a process for the synthesis of estrogen receptor modulator compounds of formula IA: 
wherein R1 is hydrogen, C1-10alkyl, C3-7cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, (hetereoaryl)alkyl or SiRaRbRc wherein said alkyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with 1, 2 or 3 groups selected from fluoro, chloro, bromo, iodo, ORd, NReRf, O(Cxe2x95x90O)NReRf, NRe(Cxe2x95x90O)Rf, NRe(Cxe2x95x90O)ORf, SRe, S(O)Re, SO2Re, SO2NReRf, LRg or MLRg;
R2 is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF3;
R3 is hydrogen, C1-10alkyl, benzyl or a removable hydroxyl protecting group;
R4 is hydrogen, fluoro, chloro, bromo, iodo, methyl or CF3;
Ra, Rb, and Rc are independently selected from C1-8alkyl, O(C1-8alkyl) and phenyl;
Rd is a removable hydroxyl protecting group, C1-10alkyl, benzyl or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C1-4alkyl, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2 or halo;
Re is C1-10alkyl or phenyl, wherein said alkyl group is optionally substituted with a group selected from O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2, phenyl or 1-5 fluoro, and wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from C1-4alkyl, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2 or halo;
Rf is C1-10alkyl or phenyl, wherein said phenyl group is substituted with 1-3 substituents independently selected from C1-4alkyl, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2 or halo;
or Re and Rf, whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;
Rg is NReRf, ORd, NRe(Cxe2x95x90O)Rf, CONReRf, SO2NReRf or a 4-9 membered mono- or bicyclic N-heterocycloalkyl ring that can be optonally substituted with 1-3 C1-3alkyl and can be optionally interrupted by O, S or NRe;
L is CH2, CReRf, or C2-6alkylene, wherein said alkylene linker can be optionally interrupted by O, S or NRe;
M is O, S, NRe, NRe(Cxe2x95x90O) or (Cxe2x95x90O)NRe;
and n is one, two or three.
In the present invention, Re and Rf, whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring. Said rings that can be formed include, but are not limited to, piperazinyl, pyridyl and pyrrolidinyl.
In the present invention, Rg can be a 4-9 membered mono- or bicyclic N-heterocycloalkyl ring that can be optonally substituted with 1-3 C1-3alkyl and can be optionally interrupted by O, S or NRe. Nonlimiting examples of said rings include pyrrolidinyl, piperidinyl, piperazinyl and morpholino.
The first step in the synthesis of compounds of formula IA comprises alkylating an indanone of formula IIA to yield an intermediate of formula IIIA. 
The alkylation is performed with an alkylating agent of formula VII in the presence of a base, 
wherein X is Br, Cl, I, OMs, OTs or OTf, and n is as defined above.
Suitable bases for the alkylation include, but are not limited to, sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide.
Next, adding a nucleophile to an intermediate of formula IIIA to yields a diene of formula IVA. 
The nucleophilic addition can be performed with an alkenyl metal species of formula VIII, 
wherein Mxe2x80x2 is MgBr, Li or Ce, and R1 is as defined above.
Next cyclizing the compound of formula IVA via a ring closing olefin metathesis reaction yields an allylic alcohol of formula VA. 
The ring closing olefin metathesis reaction is performed in the presence of a transition metal catalyst. Suitable transition metal catalysts include, but are not limited to: 
wherein 
A preferred transition metal catalyst is 
tricyclohexylphosphine[1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine ruthenium(IV) dichloride 
Other suitable catalysts for this ring closing olefin metathesis reaction are known in the art and are described in the following literature references [Angew. Chem. Int. Ed. 2002, 41, 794; J. Am. Chem. Soc. 2002, 124, 7061; Angew. Chem. Int. Ed. 2002, 41, 2403; J. Am. Chem. Soc. 2000, 122, 8168; Org. Lett. 2001, 3, 3225]. When n is 1 or 2, it is preferable to run this reaction in the presence of ethylene.
Alternatively, a chiral metathesis catalyst can be used during the ring closing olefin metathesis reaction. Suitable chiral metathesis catalysts include, but are not limited to: 
wherein 
Next, rearranging the compound of formula V via an allylic oxidative rearrangement yields the enone of formula VIA. 
The allylic oxidative rearrangement is performed with a chromium (IV) oxidant. Suitable chromium (IV) oxidants include, but are not limited to, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide and chromium trioxide-pyridine complex.
Depending on the R3 chosen, the compound of formula VIA may be equivalent to a compound of formula IA. In the case where R3 is hydrogen, final deprotection may be required to give a compound of formula IA.
The term xe2x80x9calkylxe2x80x9d shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic saturated hydrocarbon (i.e., xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94C(CH3)3, etc.).
The term xe2x80x9calkenylxe2x80x9d shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one double bond (i.e., xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, xe2x80x94CH2CHxe2x95x90C(CH3)2, etc.).
The term xe2x80x9calkynylxe2x80x9d shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one triple bond (i.e., xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94Cxe2x89xa1CCH3, xe2x80x94CH2Cxe2x89xa1CCH2(CH3)2, etc.).
The term xe2x80x9calkylenexe2x80x9d shall mean a substituting bivalent group derived from a straight or branched-chain acyclic saturated hydrocarbon by conceptual removal of two hydrogen atoms from different carbon atoms (i.e., xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2xe2x80x94, etc.).
The term xe2x80x9ccycloalkylxe2x80x9d shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a saturated monocyclic hydrocarbon (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl).
The term xe2x80x9cheterocycloalkylxe2x80x9d shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a heterocycloalkane wherein said heterocycloalkane is derived from the corresponding saturated monocyclic hydrocarbon by replacing one or two carbon atoms with atoms selected from N, O or S. Examples of heterocycloalkyl groups include, but are not limited to, oxiranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Heterocycloalkyl substituents can be attached at a carbon atom. If the substituent is a nitrogen containing heterocycloalkyl substituent, it can be attached at the nitrogen atom.
The term xe2x80x9carylxe2x80x9d as used herein refers to a substituting univalent group derived by conceptual removal of one hydrogen atom from a monocyclic or bicyclic aromatic hydrocarbon. Examples of aryl groups are phenyl, indenyl, and naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d as used herein refers to a substituting univalent group derived by the conceptual removal of one hydrogen atom from a monocyclic or bicyclic aromatic ring system containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzimidazolyl, indolyl, and purinyl. Heteraryl substituents can be attached at a carbon atom or through the heteroatom.
In the compounds of the present invention, alkyl, alkenyl, alkynyl, alkylidene, alkenylene, cycloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms by alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl, and oxo.
Whenever the term xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d or either of their prefix roots appear in a name of a substituent (e.g., aryl C1-8alkyl) it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-10) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The terms xe2x80x9carylalkylxe2x80x9d and xe2x80x9calkylarylxe2x80x9d include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, and chlorophenylethyl. Examples of alkylaryl include, but are not limited to, toluyl, ethylphenyl, and propylphenyl.
The term xe2x80x9c(heteroaryl)alkyl,xe2x80x9d as used herein, shall refer to a system that includes a heteroaryl portion, where heteroaryl is as defined above, and contains an alkyl portion. Examples of (heteroaryl)alkyl include, but are not limited to, thienylmethyl, thienylethyl, thienylpropyl, pyridylmethyl, pyridylethyl and imidazoylmethyl.
The term xe2x80x9c(cycloalkyl)alkyl,xe2x80x9d as used herein, shall refer to a system that includes a 3- to 7-membered fully saturated cyclic ring portion and also includes an alkyl portion, wherein cycloalkyl and alkyl are as defined above.
The term xe2x80x9chaloxe2x80x9d shall include iodo, bromo, chloro and fluoro.
The term xe2x80x9coxyxe2x80x9d means an oxygen (O) atom. The term xe2x80x9cthioxe2x80x9d means a sulfur (S) atom. The term xe2x80x9coxoxe2x80x9d means xe2x95x90O. The term xe2x80x9coximinoxe2x80x9d means the xe2x95x90Nxe2x80x94O group.
The term xe2x80x9cremovable hydroxyl protecting groupxe2x80x9d refers to groups which are used to protectively block the hydroxyl group during the synthesis procedures of the current invention. These conventional protecting groups are removable, i.e. they can be removed if desired by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Suitable removable hydroxyl protecting groups include the following: methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl. t-butyldimethylsilyl, and t-butyldiphenylsilyl. A comprehensive list of suitable protective groups can be found in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. 1999, the disclosure of which is incorporated herein by reference in its entirety.
The term xe2x80x9csubstitutedxe2x80x9d shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl and heteroaryl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise. For example, a C1-10alkyl may be substituted with one or more substituents selected from hydroxy, oxo, halogen, alkoxy, dialkylamino, or carboxy, and so on. In the case of a disubstituted alkyl, for instance, wherein the substituents are oxo and OH, the following are included in the definition: xe2x80x94(Cxe2x95x90O)CH2CH(OH)CH3, xe2x80x94(Cxe2x95x90O)OH, xe2x80x94CH2(OH)CH2CH(O), and so on. In the case of substituted alkyl, for instance, where the substituents are 1-5 fluoro, the following are included in the definition: xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94CF2CH3, xe2x80x94CH2CF3, xe2x80x94CF2CF3, xe2x80x94CH2CF2CH3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CF2CF3, xe2x80x94CH2CF2CH2CH3, xe2x80x94CH2CH2CF2CH3, xe2x80x94CH2CH2CF2CF3, xe2x80x94CH2CF(CH3)2, and so on. In the case cycloalkylalkyl group, for instance, wherein the substituents are 1-3 C1-3alkyl, the following are included in the definition: 
an so on
When any variable (e.g. Ra, Rb, Rc etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents indicate that the indicated bond may be attached to any of the sub-stitutable ring carbon atoms. If the ring system is polycyclic, it is intended that the bond be attached to any of the suitable carbon atoms on the proximal ring only.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase xe2x80x9coptionally substituted with one or more substituentsxe2x80x9d should be taken to be equivalent to the phrase xe2x80x9coptionally substituted with at least one substituentxe2x80x9d and in such cases the preferred embodiment will have from zero to three substituents.
Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6alkyl substituent is equivalent to 
In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2 and R3 are to be chosen in conformity with well-known principles of chemical structure connectivity.
The following specific examples are not intended to limit the present invention, but to illustrate aspects of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.